Pharmacological Manipulation of Skeletal Stem/Progenitor Cell Fate Decisions

Abstract

The mature bone houses a population of multipotent stem/progenitor cells named the skeletal stem/progenitor cells (SSPCs). Studies carried out in our lab proved the existence, in the growth plate of postnatal mice, of self-renewing putative skeletal stem cells (SSCs) thought to be involved with progenitor cells in the growth, homeostatic maintenance and repair of skeletal tissue following trauma.

As the organism ages, bone mass is lost and the prevalence of age-related conditions of the skeletal system increases. Unlike in young individuals, SSPCs are less likely to ensure perfect bone maintenance in the elderly, despite their presence in the aged bone. In the setting of this work, I hypothesized that: the decrease in their proliferative capacity as they enter senescence is responsible for the phenotypic and pathological changes observed in the bones with age; and, the pharmacological targeting of signaling pathways activated during bone development and growth can change SSPCs fate decisions, alleviate age-related bone loss and modify the pathological outcome in the aging organisms. I pursued the following aims: 1) to study SSPCs proliferation and senescence in aged mice; 2) to pharmacologically manipulate SSPCs fate decisions.

With methods involving lineage tracing and imaging cytometry, the conducted experiments showed that the SSPC population shrinks in aged mice growth plate and their proliferation and senescence levels decrease. Of the compounds tested, 20(S)-hydroxycholesterol, a Hedgehog pathway agonist, keeps SSPCs quiescent/non-proliferative in vitro; and tamoxifen exerts a sex-dependent effect on growth plate chondrocytes (including SSPCs) in vivo. Tamoxifen stimulates chondrocytes proliferation and senescence entry in male mice, while protecting them from senescence in female mice.

This is the first report of its kind on the Sox9+ SSPC population. More in-depth investigations into the specific mechanisms of action of these compounds are necessary.

This work brings us closer to our goal of addressing acute and chronic age-related conditions of the skeletal system with novel stem-cell based therapies.